This invention relates generally to catalysis of enantioselective reactions, and more particularly relates to the use of chiral organic compounds as catalysts for a variety of reactions involving xcex1,xcex2-unsaturated aldehydes as reactants.
Ancillary (or xe2x80x9cspectatorxe2x80x9d) ligand-metal coordination complexes (e.g., organometallic complexes) and compositions are useful as catalysts, stoichiometric reagents and therapeutic agents. The ancillary ligand contains functional groups that bind to one or more metal centers and remain associated therewith, providing an opportunity to modify the steric, electronic and chemical properties of the active sites of the complex, i.e., the metal centers.
Unfortunately, many organometallic reagents are expensive and depending on their catalytic activity may not be commercially viable. Moreover, many organometallic complexes are useful only for very specific chemical reactions and do not have broad utility as catalysts for a variety of different types of reactions. This problem may be emphasized for the catalysis of reactions leading to chiral molecules, particularly the conversion of either chiral or a chiral molecules via enantioselective catalysis to provide a chiral product.
Over the last 30 years enantioselective catalysis has become one of the most important frontiers in exploratory organic synthetic research. In the pharmaceutical industry and other industries, the use of pure enantiomeric molecules is often important for safety and efficacy. Thus, in the production of pharmaceuticals, use of catalysts or reagents that preferentially produce one enantiomer of a molecule relative to another enantiomer is particularly advantageous. Unfortunately, the catalysts that produce such enantiomers are typically organometallic complexes that are specific for a particular reaction. In addition, there is no way to predict with any reasonable accuracy which enantiomer will result. Examples of organometallic catalysts used to prepare chiral materials include BINOL-based complexes (Mikami et al. (1994) J. Am. Chem. Soc. 116:2812; Kobayashi et al. (1994) J. Am. Chem. Soc. 116:4083; Mikami et al. (1989) J. Am. Chem. Soc. 111:1940; Mikami et al. (1994) J. Am. Chem. Soc. 116:4077; Keck et al. (1993) J. Am. Chem. Soc. 115:8467; Keck et al. (1995) J. Am. Chem. Soc. 117:2363), BINAP-based complexes (Miyashita et al. (1980) J. Am. Chem. Soc. 102:7932; Miyashita et al. (1984) Tetrahedron 40:1245; Takaya et al. (1986) J. Org. Chem. 51:629; Takaya et al. (1988) Org. Synth. 67:20; Cai et al. (1995) Tetrahedron Lett. 36:7991), DUPHOS complexes (Burk et al. (1990) Organometallics 9:2653; Burk et al. (1993) J. Am. Chem. Soc115:10125; Burk et al. (1992) J. Am. Chem. Soc. 114:6266; Burk et al. (1995)J. Am. Chem. Soc. 117:9375); salen-based complexes (i.e., organometallic complexes containing the N,N-bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexane-diamino ligand; see, e.g., Li et al. (1993) J. Am. Chem. Soc115:5326, and Evans et al. (1993) Tetrahedron Lett. 34:7027), and bisoxazoline-containing compounds (Evans et al. (1993) J. Am. Chem. Soc. 115:6460; Evans et al. (1997) J. Am. Chem. Soc. 119:7893; Evans et al. (1996) Tetrahedron Lett. 37:7481; Corey et al. (1992) Tetrahedron Lett. 33:6807; Gothelfet al. (1996) J. Org. Chem. 61:346).
Despite the observed need and relatively few, narrow solutions, relatively few asymmetric transformations have been reported which employ organic molecules as reaction catalysts. There is tremendous potential for academic, economic and environmental benefit should versatile, chiral organic catalysts be developed. Only a few researchers have disclosed organic catalysts useful for preparing chiral materials. See, e.g., Asymmetric Catalysis in Organic Synthesis, Noyori, R., Ed. (New York: Wiley, 1994) and Asymmetric Synthesis, Ojima, I., Ed. (New York: VCH, 1993), and references cited therein. Also see Yang et al. (1998) J. Am. Chem. Soc. 120(24):5943-5952, who disclose the use of a dioxirane to catalyze enantioselective epoxidation, Shi et al. (1995) J. Chem. Research (S):46-47 (J. Chem. Research (M): 0401-0411), who disclose preparation of chiral quaternary ammonium salts stated to be useful as chiral phase-transfer catalysts by reaction of (R)-(+)-2,2-bis(bromomethyl)-6,6-dinitrobiphenyl and (R)-(+)-2,2-bis(bromomethyl)-1,1-binaphthyl with cyclic amines such as pyrrolidine, piperidine and 4-hydroxypiperidine. International Patent Publication No. WO 92/02505 to Castelijns also discloses use of a secondary amine in a catalytic transformation, i.e., in conversion of an unsaturated imine to a pyridine product, by reaction with an aldehyde or ketone.
Recently, however, certain organic catalysts have been disclosed as generally useful in a variety of enantioselective transformations, by lowering the LUMO (lowest unoccupied molecular orbital) of a reactant to facilitate reaction thereof. The organic catalysts are acid addition salts of nonmetallic compounds containing a Group 15 or Group 16 heteroatom, e.g., chiral amines, exemplified by the imidazolidinone salt (5S)-5-benzyl-2,2,3-trimethylimidazolidin-4-one hydrochloride (I) 
while exemplary reactants are xcex1,xcex2-unsaturated carbonyl compounds, including xcex1,xcex2-unsaturated aldehydes as well as xcex1,xcex2-unsaturated ketones. Such catalysts and reactions are described in U.S. Pat. No. 6,307,057 to MacMillan and U.S. Pat. No. 6,369,243 to MacMillan et al., which disclose the utility of (I) and other chiral amine salts in catalyzing a variety of reactions, including cycloaddition reactions, 1,4 nucleophile conjugate addition reactions, 1,4 radical addition reactions, organometallic insertion reactions, and ene reactions.
The use of catalyst (I) in the LUMO-lowering activation of xcex1,xcex2-unsaturated aldehydes, in particular, has been reported by Ahrendt et al. (2000) J. Am. Chem. Soc. 122:4243-4244, Jen et al. (2000) J. Am. Chem. Soc. 122:9874-9875, and Paras et al. (2001) J. Am. Chem. Soc. 123:4370-4371. The reaction proceeds via the reversible formation of an iminium ion intermediate, which can be in one of two enantiomeric configurations. Using propenal as a reactant and (I) as the catalyst, the possible iminium ion intermediates A and B are formed (Equation 1): 
Upon further reaction, e.g., with cyclopentadiene in a Diels-Alder reaction, each intermediate results in a different enantiomeric product. That is, intermediate A gives rise to an exo product, while intermediate B results in the endo product (Equation 2): 
While imidazolidinone salt (I) and other chiral amines described in the foregoing references are quite valuable as enantioselective organic catalysts, there is a continuing need for nonmetallic catalysts that exhibit even higher levels of enantioselectivity across a diverse range of carbon-carbon bond forming reactions involving xcex1,xcex2-unsaturated carbonyl compounds as reactants. An ideal catalyst would be inexpensive and straightforward to synthesize, compatible with aerobic conditions, and provide for efficient reaction rates, good control over the geometry of the iminium ion intermediate, and high levels of enantiofacial discrimination. The invention is, in part, directed to such novel catalysts.
The invention is also directed to use of the novel catalysts in the alkylation of indoles and other bicyclic and polycyclic molecules containing at least one N-heterocyclic ring. With the commercial success of chiral pharmaceuticals has come an increasing demand for enantioselective methods to access structural motifs of established value in medicinal chemistry, and the indole structure has become widely identified as a xe2x80x9cprivileged pharmacophorexe2x80x9d with implementation in over 40 medicinal agents of diverse therapeutic action. See Kleeman et al., Pharmaceutical Substances 4th Ed.; Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Thieme: Stuttgart, New York, 2001. Surprisingly, however, asymmetric entry to indolic architecture has been largely restricted to either the derivatization of enantiopure amino acids such as tryptophan (as in the synthesis of oxitriptan, or 5-hydroxytryptophan, the precursor to serotonin) or the optical resolution of racemic mixtures (as in the preparation of ramosetron, a 5-HT3 antagonist; see Ohta et al. (1996) Chem. Pharm. Bull. 44:1707).
In one aspect of the invention, then, novel chiral catalysts are provided that address the aforementioned needs in the art, by enabling enantioselective reaction of xcex1,xcex2-unsaturated carbonyl compounds, particularly xcex1,xcex2-unsaturated aldehydes. The catalysts are nonmetallic, organic compounds, and thus avoid the problems associated with traditional organometallic catalysts. The present catalysts are readily synthesized from inexpensive, commercially available reagents, are compatible with aerobic conditions, and provide the desired products in excellent yields with a high level of enantioselectivity. The chiral catalysts are imidazolidinone compounds having the structure of formula (IIA) or (IIB) 
wherein:
R1 is selected from the group consisting of C1-C12 hydrocarbyl, substituted C1-C12 hydrocarbyl, heteroatom-containing C1-C12 hydrocarbyl, and substituted heteroatom-containing C1-C12 hydrocarbyl;
R2 has the structure xe2x80x94(L)mxe2x80x94CR6R7R8 wherein m is zero or 1, L is C1-C6 alkylene, and R6, R7 and R8 are C1-C12 hydrocarbyl;
R3 and R4 are independently selected from the group consisting of hydrogen, halo, hydroxyl, C1-C12 hydrocarbyl, substituted C1-C12 hydrocarbyl, heteroatom-containing C1-C12 hydrocarbyl, and substituted heteroatom-containing C1-C12 hydrocarbyl; and
R5 is a cyclic group optionally substituted with 1 to 4 non-hydrogen substituents and containing zero to 3 heteroatoms,
and also include acid addition salts thereof.
In another aspect of the invention, a process is provided for using imidazolidinone (IIA) or (IIB) to catalyze a reaction between an xcex1,xcex2-unsaturated aldehyde and a second reactant by lowering the energy level of the lowest unoccupied molecular orbital (LUMO) of the aldehyde. The process involves contacting an xcex1,xcex2-unsaturated aldehyde with the second reactant in the presence of (IIA) or (IIB), either in the form of an acid addition salt, or in the form of an electronically neutral compound combined with an acid.
The xcex1,xcex2-unsaturated aldehyde has the structure of formula (III) 
in which R9, R10 and R11 are independently selected from the group consisting of hydrogen, C1-C30 hydrocarbyl, heteroatom-containing C1-C30 hydrocarbyl, substituted C1-C30 hydrocarbyl, substituted heteroatom-containing C1-C30 hydrocarbyl, and functional groups. The second reactant may be any compound that is capable of reacting with the xcex1,xcex2-unsaturated aldehyde by virtue of the lowered LUMO of the carbon-carbon double bond within the aldehyde in the presence of the imidazolidinone catalyst. The second reactant may or may not be covalently linked, directly or indirectly, to the first reactant, i.e., the reaction between the xcex1,xcex2-unsaturated aldehyde and the second reactant may be either intramolecular or intermolecular. Selection of the second reactant will depend on the reaction of interest; thus, for example, in a Diels-Alder reaction, the second reactant is a diene, while the first reactant, i.e., the xcex1,xcex2-unsaturated aldehyde, serves as a dienophile.
Examples of such reactions that may be catalyzed using the present compounds and methods include, without limitation, cycloaddition reactions, 1,4-nucleophile conjugate addition reactions, 1,4 radical addition reactions, organometallic insertion reactions (including Heck reactions), ene reactions, and any combination thereof (including reactions occurring in tandem or cascade).
Cycloaddition reactions include, for example, [2+2] cycloaddition, [3+2] cycloaddition and [4+2] cycloaddition, with the latter reactions exemplified by Diels-Alder reactions, inverse demand Diels-Alder reactions, and hetero Diels-Alder reactions. Other types of cycloaddition reactions that can be catalyzed using the compositions and methods of the invention are described, for example, by Gothelf et al. (1998) Chem. Rev. 98:863-909.
1,4 Nucleophile conjugate addition reactions, include 1,4 carbon addition (e.g., cyclopropanation), 1,4 amine addition (e.g., aziridination), 1,4 oxygen addition (e.g., epoxidation), 1,4 sulfur addition, 1,4 hydride addition, and 1,4 organometallic addition. Such reactions are examples of Michael additions, wherein the second reactant is a nucleophile containing a xcfx80 bond, a lone pair bearing heteroatom, or a negative charge.
In a further aspect of the invention, the chiral catalysts of the invention are used in the alkylation of nitrogen-containing heterocycles, particularly bicyclic and polycyclic compounds containing at least one N-heterocyclic ring. Such reactants include, by way of example, compounds having the structure of formula (IV) 
wherein:
R12 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl;
Q is a five- or six-membered aromatic ring containing zero to 3 heteroatoms selected from N, O and S and zero to 4 nonhydrogen substituents, wherein any two adjacent nonhydrogen substituents may together form an additional aryl, substituted aryl, heteroaryl, or heteroaryl substituent; and
X is N or CR13 wherein R13 is hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl.
In one preferred embodiment of the aforementioned reaction, compound (IV) is substituted at the 3-position with a moiety xe2x80x94L1xe2x80x94Nu: (i.e., X is CR13 where R13 is xe2x80x94L1xe2x80x94Nu:) wherein L1 is a hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene linker with 2 to 6 atoms in the linker backbone, and Nu: is a nucleophilic group capable of addition to an unsaturated bond, e.g., secondary amino, hydroxyl, or sulfhydryl, with secondary amino groups (including xe2x80x94NH-Prot wherein Prot is an amine protecting group such as butyloxycarbonyl, or xe2x80x9cBOCxe2x80x9d) most preferred. The xe2x80x94L1xe2x80x94Nu: substituent enables a subsequent reaction step in which Nu: adds to the double bond of the pyrrole ring. This cycloaddition step, following the initial reaction of compound (IV) with the xcex1,xcex2-unsaturated aldehyde, enables the straightforward synthesis of a variety of polycyclic compounds, including, by way of example, pyrroloindolines, a core structure having extensive utility in the development of a wide variety of therapeutic agents.